Microglia, the resident immune cells of the central nervous system, exhibit dynamic morphological and functional changes in response to environmental signals, particularly during neuroinflammatory processes. Recent studies have highlighted the role of neuronal micronuclei in regulating microglial characteristics, indicating that these cellular components can influence microglial differentiation during the postnatal period (ref: Yano doi.org/10.1038/s41593-024-01863-5/). Additionally, engineered extracellular vesicles (EVs) have emerged as a promising therapeutic strategy, where mRNA delivery via EVs has been shown to modulate microglial function and alleviate depressive-like behaviors, suggesting a novel approach to treating neuroinflammation associated with mood disorders (ref: Ge doi.org/10.1002/adma.202418872/). Furthermore, the protein kinase C modulator bryostatin-1 has demonstrated potential in shifting microglial phenotypes from pro-inflammatory to regenerative states, thereby promoting remyelination in multiple sclerosis models (ref: Gharibani doi.org/10.1126/scitranslmed.adk3434/). The Human Microglia Atlas (HuMicA) has provided significant insights into the heterogeneity of microglial populations across various neurodegenerative diseases, revealing nine distinct microglial subsets that are differentially activated in conditions such as Alzheimer's disease and multiple sclerosis (ref: Martins-Ferreira doi.org/10.1038/s41467-025-56124-1/). Moreover, the activation of the NLRP3 inflammasome in microglia has been implicated in impairing blood-brain barrier integrity during peripheral inflammation, highlighting the complex interplay between microglial activation and neuroinflammatory responses (ref: Yoon doi.org/10.1038/s41467-025-56097-1/). These findings underscore the critical role of microglia in neuroinflammation and their potential as therapeutic targets in neurodegenerative diseases.

Neurodegenerative diseases are characterized by complex interactions between pathological proteins and microglial responses. For instance, the ApoE3 R136S variant has been shown to bind Tau protein, inhibiting its propagation and reducing neurodegeneration in Alzheimer's disease models (ref: Chen doi.org/10.1016/j.neuron.2024.12.015/). This protective mechanism highlights the importance of genetic factors in modulating microglial responses to neurodegenerative processes. Additionally, the gut microbiome has been implicated in glioma progression, with specific bacterial populations influencing immune cell infiltration and tumor dynamics, suggesting that environmental factors can significantly affect neurodegenerative disease outcomes (ref: Chatterjee doi.org/10.1093/neuonc/). Moreover, recent research has elucidated the role of nonapoptotic caspase-3 in driving microglial synaptic phagocytosis, indicating that microglial activity is not solely reactive but can also be a regulated process that contributes to synaptic health (ref: Andoh doi.org/10.1038/s41467-025-56342-7/). The correlation between regional brain iron levels and transcriptional signatures in Alzheimer's disease further emphasizes the multifaceted nature of microglial involvement in neurodegeneration, where iron accumulation is linked to inflammatory processes and cellular dysfunction (ref: Yang doi.org/10.1002/alz.14459/). These findings collectively underscore the intricate relationship between microglial function and neurodegenerative disease pathology, revealing potential avenues for therapeutic intervention.

Microglia play a pivotal role in mediating immune responses within the central nervous system, and recent studies have explored various mechanisms by which they interact with other cell types. For example, microglia-derived interleukin-6 (IL-6) has been shown to trigger astrocyte apoptosis, contributing to depression-like behaviors in animal models (ref: Shen doi.org/10.1002/advs.202412556/). This highlights the importance of microglial signaling in modulating neuroinflammatory responses and the potential for targeting these pathways in treating mood disorders. Additionally, the activation of the NLRP3 inflammasome in microglia has been linked to blood-brain barrier disruption, emphasizing the role of microglial activation in neuroinflammation and its consequences for neuronal health (ref: Yoon doi.org/10.1038/s41467-025-56097-1/). Furthermore, the interplay between astrocytes and microglia has been investigated in the context of sepsis-associated encephalopathy, where astrocyte-derived IL-11 was found to modulate crosstalk between these cell types via the NF-κB signaling pathway (ref: Zhu doi.org/10.34133/research.0598/). This suggests that therapeutic strategies aimed at enhancing beneficial astrocyte-microglia interactions could be beneficial in neuroinflammatory conditions. The characterization of oxidative stress induced by amyloid-beta oligomers in mixed glial cultures also underscores the critical role of microglia in managing oxidative damage and supporting neuronal function (ref: Cardaci doi.org/10.1016/j.freeradbiomed.2025.01.030/). Collectively, these studies illustrate the complex immune interactions involving microglia and their implications for neuroinflammatory diseases.

Innovative therapeutic strategies targeting microglial function have gained traction in recent research, particularly in the context of neurodegenerative diseases and brain injuries. Engineering extracellular vesicles (EVs) for mRNA delivery has emerged as a promising approach to modulate microglial activity and alleviate depressive-like behaviors, showcasing the potential of mRNA therapy in treating neuroinflammatory conditions (ref: Ge doi.org/10.1002/adma.202418872/). Additionally, the development of bFGF-Chitosan 'brain glue' has demonstrated efficacy in promoting functional recovery following cortical ischemic stroke by enhancing angiogenesis and neurogenesis, indicating that microglial modulation can facilitate brain repair processes (ref: Mu doi.org/10.1016/j.bioactmat.2024.12.017/). Moreover, the regulation of neuroinflammation and phagocytosis by chitinase 1 (CHIT1) has been shown to suppress amyloid-beta plaque deposition in Alzheimer's disease models, highlighting the therapeutic potential of targeting microglial functions to mitigate disease progression (ref: Yuan doi.org/10.1002/path.6387/). These findings suggest that therapeutic strategies aimed at modulating microglial responses can significantly impact the course of neurodegenerative diseases and brain injuries, paving the way for novel treatment paradigms.

The genetic and molecular underpinnings of microglial function are critical for understanding their role in neurodegenerative diseases. Recent studies have identified the protective effects of the ApoE3 R136S variant against Alzheimer's disease, demonstrating its ability to bind Tau and inhibit its propagation, thereby reducing neurodegeneration (ref: Chen doi.org/10.1016/j.neuron.2024.12.015/). This highlights the significance of genetic factors in modulating microglial responses to pathological proteins. Furthermore, the role of nonapoptotic caspase-3 in facilitating microglial synaptic phagocytosis underscores the importance of molecular signaling pathways in regulating microglial activity during neurodegenerative processes (ref: Andoh doi.org/10.1038/s41467-025-56342-7/). The Human Microglia Atlas (HuMicA) has provided a comprehensive overview of microglial heterogeneity across various neurodegenerative conditions, revealing distinct transcriptional profiles associated with different microglial subsets (ref: Martins-Ferreira doi.org/10.1038/s41467-025-56124-1/). Additionally, the activation of the NLRP3 inflammasome in microglia has been linked to blood-brain barrier impairment, emphasizing the role of inflammatory signaling in neurodegenerative disease progression (ref: Yoon doi.org/10.1038/s41467-025-56097-1/). These insights into the genetic and molecular mechanisms governing microglial function are essential for developing targeted therapies aimed at modulating their activity in neurodegenerative diseases.

Microglia play a crucial role in the brain's response to injury and repair mechanisms. Recent studies have highlighted the potential of engineered extracellular vesicles (EVs) to regulate microglial function and promote recovery following brain injuries, such as ischemic stroke (ref: Ge doi.org/10.1002/adma.202418872/). The use of bFGF-Chitosan 'brain glue' has shown promise in enhancing functional recovery by promoting angiogenesis and neurogenesis, indicating that microglial modulation can facilitate brain repair processes (ref: Mu doi.org/10.1016/j.bioactmat.2024.12.017/). Moreover, the regulation of neuroinflammation and phagocytosis by chitinase 1 (CHIT1) has been demonstrated to suppress amyloid-beta plaque deposition in Alzheimer's disease models, further emphasizing the therapeutic potential of targeting microglial functions to mitigate disease progression (ref: Yuan doi.org/10.1002/path.6387/). The characterization of oxidative stress induced by amyloid-beta oligomers in mixed glial cultures also underscores the critical role of microglia in managing oxidative damage and supporting neuronal function (ref: Cardaci doi.org/10.1016/j.freeradbiomed.2025.01.030/). Collectively, these findings illustrate the multifaceted role of microglia in brain injury and repair, highlighting their potential as therapeutic targets in neurodegenerative diseases.

Microglial responses to environmental factors are critical in shaping their function and influence on neuroinflammatory processes. Recent research has shown that the ocular inflammatory response to adeno-associated virus (AAV) gene therapy varies significantly by age and sex, indicating that these demographic factors can modulate microglial activation and inflammatory responses (ref: Clare doi.org/10.1016/j.ymthe.2025.01.028/). This highlights the importance of considering individual variability in preclinical studies of gene therapies. Additionally, the regulation of neuroinflammation and phagocytosis by chitinase 1 (CHIT1) has been shown to suppress amyloid-beta plaque deposition in Alzheimer's disease models, emphasizing the role of microglia in responding to pathological stimuli (ref: Yuan doi.org/10.1002/path.6387/). The interplay between oxidative stress induced by amyloid-beta oligomers and microglial function further underscores the critical role of microglia in managing environmental stressors and supporting neuronal health (ref: Cardaci doi.org/10.1016/j.freeradbiomed.2025.01.030/). These findings collectively illustrate the complex interactions between microglia and environmental factors, underscoring their significance in neuroinflammatory diseases.